Primecuts – This Week In The Journals

November 10, 2014

By Shannon Chiu, MD

Peer Reviewed

This past Tuesday’s midterm congressional elections proved to be a big day for the Republicans, as they took control of the Senate and a record number of governor’s seats, and expanded their majority in the House – their largest House majority since World War II era. President Obama shook off his party’s electoral drubbing, noting that he was eager to find common ground with the Republicans: “It doesn’t make me mopey. It energizes me, because it means that this democracy’s working.” [1]

In other news, Ebola continues to preoccupy our minds. According to the situation report released by the World Health Organization this week, a total of 13,042 confirmed, probable, and suspected cases of Ebola have been found in 8 affected countries as of Nov 2, with 4,818 reported deaths. The weekly incidence in Sierra Leone continues to rise. Of note, all 83 contacts of the healthcare worker infected in Madrid, Spain, have completed the 21-day follow-up period. [2] President Obama is asking Congress for $6 billion in emergency funding to combat this fatal disease.

Dengue prevention – a new hope on the horizon

In related news of infectious disease, dengue has become an increasing public health problem, with 5-fold increase in number of cases from 2003 to 2013 reported to Pan American Health Organization [3]. This week’s NEJM brings us a randomized, blinded, placebo-controlled efficacy phase 3 trial involving over 20,000 children ages 9-16 in five Latin American countries [4]. The vaccine consists of 4 recombinant dengue vaccine viruses (CYD 1-4). Children were scheduled for visits at months 0, 6, and 12 for vaccination, and at month 13 for follow-up and blood sampling. Overall there were 176 cases of dengue in the vaccine group and 221 in the control group in the per-protocol population. Villar et al. found a vaccine efficacy of 60.8% (95% CI, 52.0 to 68.0) against symptomatic virologically confirmed dengue in a per-protocol analysis. Serotype-specific efficacies for serotypes 1-4 were 50.3%, 42.3%, 74.0%, and 77.7%, respectively. Secondary outcomes included efficacy against hospitalizations after at least 1 injection [80.3% (95% CI, 64.7 to 89.5)] and severe dengue after the first injection [95.5% (95% CI, 68.8 to 99.9)]. No significant risk was found of administering dengue vaccine to children with mix of seropositive and seronegative status.

Overall reduction in severity of clinical disease, prevention of hospitalization, and per-protocol efficacy are encouraging. Villar et al. provide the third major dengue vaccine trial in the last decade, the other two being the phase 2b efficacy trial in Thailand [5] and the first phase 3 trial in Asia [6]. Vaccine safety and immunogenicity were consistent across the three trials. However, variable serotype-specific efficacy raises interesting question of how preexisting immunity interferes with a serotype-specific vaccine response.

Single agent vs. combination for HIV-1 prophylaxis

In more infectious disease news, combination ART is critical for those with HIV-1 infection, but more than one agent may not be necessary for effective pre-exposure prophylaxis (PrEP). Baeten et al. [7] report in this week’s Lancet Infectious Disease their latest results of a multisite, randomized, double-blind, placebo-controlled phase 3 trial. 4,427 participants were heterosexual couples from Kenya and Uganda, who were HIV-1 serodiscordant. Tenofovir disoproxil fumarate (300 mg) alone, or in combination with emtricitabine (200 mg), was given orally at the doses approved for treatment of HIV-1. Overall, there was no significant difference in HIV-1 seroconversions between the two groups (p=0.08; HR 0.64, 95% CI 0.39 to 1.06) in the intention-to-treat analysis. Having detectable tenofovir, compared with undetectable tenofovir, was associated with an estimated relative risk reduction for acquiring HIV-1 of 85% for tenofovir disoproxil fumarate and 93% for emtricitabine plus tenofovir disoproxil fumarate (both p<0.0001), with no significant difference between the two (pinteraction=0.34). No significant differences were found in death frequency or serious adverse events between the two cohorts.

That single-agent tenofovir had comparable protective effects of HIV-1 compared with emtricitabine plus tenofovir, has important implications for policy makers, costs, safety, and decreasing resistance to multi-agent therapy. For HIV-1 serodiscordant couples, PrEP is a critical HIV-1 prevention measure via the uninfected partner, especially in couples where the infected partner declines ART.

Major cardiac events after hospitalization for infective endocarditis

Shifting gears, this week’s Circulation reports a retrospective cohort study by Shih et al. [8], looking at specific major adverse events of patients after hospitalization for infective endocarditis (IE). Shih et al. used Taiwan’s National Health Insurance Research Database to conduct a nationwide population-based, observational retrospective cohort study, consisting of IE cohort and matched cohort without IE, between January 2000 and December 2009. The IE cohort of 8,494 patients had higher rates of major cardiac adverse events across all primary outcomes, with adjusted hazard ratios (HR) of 1.59 (95% CI, 1.40–1.80) for ischemic stroke, 2.37 (95% CI, 1.90–2.96) for hemorrhagic stroke, 1.44 (95% CI, 1.17–1.79) for myocardial infarction, 2.24 (95% CI, 2.05–2.43) for readmission for heart failure, 1.69 (95% CI, 1.44–1.98) for sudden cardiac death or ventricular arrhythmia, and 2.27 (95% CI, 2.14–2.40) for all-cause death. Recurrent IE was observed in 11.7% of patients, of which 56.5% had recurrence within first year. Repeat IE itself also increased the subsequent risk of hemorrhagic stroke and myocardial infarction.

While the study is not without limitations (such as failure to include in the cohort search patients’ smoking history, BMI, EtOH use; incomplete documentation of the culprit organisms in IE patients in the database), this study highlights the significant increased risk of major cardiac events, as well as high risk of IE recurrence, prompting the need for long-term surveillance beyond the first year after discharge for IE.

Non-obstructive CAD is not insignificant

Despite the prevalence of non-obstructive CAD – found in 10-25% of patients undergoing coronary angiography – most studies have focused on patients with MI and obstructive CAD. In this week’s JAMA Maddox et al. [9] conducted a retrospective study to assess CAD extent (across the continuum of non-obstructive to obstructive disease) on MI incidence and all-cause mortality. Data were collected from ~40,000 veterans between Oct 2007 and Sep 2012. Within the cohort, 22.3% had non-obstructive CAD on elective coronary angiography, 55.4% had obstructive CAD, and the remaining 22.3% had no apparent CAD. Those with non-obstructive CAD had a 2- to 4.5-fold greater risk for MI compared to those without evidence of CAD. Interestingly, 1-year MI risk increased progressively by CAD extent, and did not increase abruptly when CAD became obstructive (ranging from 0.11% among patients with no apparent CAD to 2.47% with 3-vessel or left main obstructive CAD). One-year mortality rates also increased with increasing CAD extent, ranging from 1.38% in patients without apparent CAD to 4.30% in those with 3-vessel or left main obstructive CAD.

Study limitations included selection bias for those undergoing elective coronary angiogram, lack of cardiac-specific mortality data, and limited generalizability, as cohort was predominantly male and white. Nevertheless, this study highlights the notion that non-obstructive lesions are not “insignificant,” which can otherwise mislead patients into thinking that they are not at risk.

In other news …

A randomized, superiority trial published in the NEJM, examined the use of rituximab vs. azathioprine for maintenance treatment in ANCA-associated vasculitis [10]. While the two groups had similar frequencies of severe adverse events, more patients had sustained remission at month 28 with rituximab than with azathioprine (p<0.01).

Genetic factors may play a key role in the development of a wide range of responses to the Ebola virus. A newly developed mouse model reported in Science [11] examines how disease outcomes and variations in mortality rates correlate with specific genetic lines of mice, as conventional laboratory mice previously infected with Ebola virus would die but not develop symptoms of Ebola hemorrhagic fever. The researchers bred and tested different mouse strains from the “Collaborative Cross” for Ebola susceptibility, identifying at least one susceptibility allele, Tek, involved in coagulopathy, endothelial activation, and vascular integrity and regulation.

While axillary lymph node dissection is the standard treatment for breast cancer patients with positive sentinel node, a recent trial published in Lancet Oncology reported comparable outcomes (i.e. 5-year axillary recurrence, disease-free survival) for patients with T1-2 primary breast cancer treated with axillary lymph node dissection vs. axillary radiotherapy, with the latter resulting in significantly less morbidity (i.e. lymphedema). [12]

With increasing literature on medical errors associated with resident handoffs, NEJM published a prospective intervention study, implementing the “I-PASS Handoff Bundle” in 9 pediatric residency programs. [13] This “bundle” composed of 7 elements, including the I-PASS pneumonic (illness severity, patient summary, action list, situation awareness and contingency plans, and synthesis by receiver); 2-hour workshop; direct-observation by faculty, and more. The investigators found a significant reduction in medical errors and rate of preventable adverse events, without associated change in duration of oral handoffs or resident workflow.

Dr. Shannon Chiu is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Karin Katz, M.D., Internal Medicine Resident, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


1. Hirschfeld Davis J., Baker P. (2014, November 5). After Election, Obama Vows to Work With, and Without, Congress. The New York Times. Retrieved November 6, 2014, from

2. WHO Ebola Response Roadmap Situation Report (2014, November 5). Retrieved November 6, 2014, from

3. Zambrano B, San Martin JL. Epidemiology of dengue in Latin America. J Pediatric Infect Dis Soc. 2014;3:181-182.

4. Villar L, Dayan GH, Arredondo-Garcia JL, et al. Efficacy of a tetravalent dengue vaccine in children in Latin America. NEJM. Epub ahead of print.

5. Sabchareon A, Wallace D, Sirivichayakul C, et al. Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. Lancet. 2012;380:1559–1567.

6. Capeding MR, Tran NH, Hadinegoro SR, et al. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet. 2014;384:1358-1365.

7. Baeten JM, Donnell D, Mugo NR, et al. Single-agent tenofovir versus combination emtricitabine plus tenofovir for pre-exposure prophylaxis for HIV-1 acquisition: an update of data from a randomised, double-blind, phase 3 trial. Lancet Infectious Disease. 2014;14(11):1055-1064.

8. Shih C-J, Chu H, Chao P-W, et al. Long-Term Clinical Outcome of Major Adverse Cardiac Events in Survivors of Infective Endocarditis. Circulation. 2014;130:1684-1691.

9. Maddox TM, Stanislawski MA, Grunwald GK, et al. Nonobstructive Coronary Artery Disease and Risk of Myocardial Infarction. JAMA. 2014;312(17):1754-1763.

10. Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus Azathioprine for maintenance in ANCA-associated vasculitis. NEJM. 2014;317(19): 1771-1780.

11. Rasmussen AL, Okumura A, Ferris MT, et al. Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance. Science. 2014(Published Online).

12. Donker M, van Tienhoven G, Straver ME, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncology. 2014;15(12):1303-1310.

13. Starmer AJ, Spector ND, Strivastava R, et al. Changes in medical errors after implementation of a handoff program. NEJM. 2014;371(19): 1803-1812.